Transarterial Chemoembolization Combined with Regorafenib and PD-1 Inhibitor as Second-Line Therapy for Unresectable Hepatocellular Carcinoma

Di Wang,1,* Wei Zhang,2,* Xudong Gao,2 Huifang Kong,2 Huixin Zhang,2 Jiagan Huang,2 Meng Zhang,1 Xiujuan Chang,2 Zhen Zeng1,2 1 302 Clinical Medical School, Peking University, Beijing, People’s Republic of China; 2Senior Department of Liver Disease Medicine, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen Zeng, 302 Clinical Medical School, Peking University, Beijing, People’s Republic of China, Email zengzhen1970@sina.com Xiujuan Chang, Senior Department of Liver Disease Medicine, Chinese PLA General Hospital, Beijing, People’s Republic of China, Email 154260198@qq.comAim: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) plus regorafenib and PD-1 inhibitor (T-R-P) versus regorafenib plus PD-1 inhibitor (R-P) as the second-line treatment for unresectable hepatocellular carcinoma (uHCC).Methods: In this retrospective, single-center cohort study, 130 uHCC patients who received second-line therapy between February 2020 and July 2024 were enrolled. Among the 130 enrolled patients, 69 received T-R-P and 61 received R-P. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were used to minimize confounding factors. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Multivariate Cox regression analysis was used to identify prognostic factors. Subgroup analyses were conducted to assess the treatment benefits in specific patient populations.Results: After PSM, the T-R-P regimen showed significantly improved OS (14.3 vs 8.1 months) and PFS (8.4 vs 4.3 months) compared to the R-P regimen (P < 0.001). According to mRECIST, ORR (56.5% vs 15.2%) and DCR (69.6% vs 37.0%) were also significantly higher with the T-R-P regimen. Multivariate Cox regression analysis identified the T-R-P regimen as an independent protective factor for both OS (hazard ratio [HR] = 0.33, P < 0.001) and PFS (HR = 0.39, P < 0.001). These consistent survival benefits in the T-R-P regimen were maintained in both the unmatched cohort and after IPTW. Subgroup analyses further confirmed the consistent survival benefits of the T-R-P regimen across the most predefined patient subgroups. No treatment-related deaths occurred during the study period.Conclusion: After PSM, the T-R-P regimen continued to demonstrate statistically significant and clinically meaningful improvements in both OS and PFS, coupled with a manageable safety profile, compared to the R-P regimen in patients with uHCC. These findings provide a rationale for considering the T-R-P regimen as a potential second-line treatment option.Keywords: unresectable hepatocellular carcinoma, transarterial chemoembolization, PD-1 inhibitor, regorafenib, second-line therapy